Pyrrolobenzodiazepines (PBD) and dimers thereof are known to interact with DNA and are effective cancer chemotherapy agents. Problematically, side effects associated with some PBDs, such as cardiotoxicity and acute tissue necrosis have limited use, dosage and effectiveness.
Conjugates comprising a selective carrier-linker-PBD structure (e.g., an antibody-PBD conjugate (ADC)), are attractive selective chemo-therapeutic molecules, as they combine ideal properties of selectivity to a target cell and cytotoxic drugs. By directing potent cytotoxic drugs to a target cell, the desired therapeutic effect may be improved in the target cell while minimizing the effect on non-targeted cells. Examples of such improvements include reduced dose required to achieve a therapeutic effect, targeted delivery, and improved bloodstream stability. Nonetheless, PBD ADCs may still present adverse side effects that limit use and/or dosage.
A need therefore exists for PBD compounds and formulations that provided for reduced toxicity and improved bioefficacy.